Synthesis & Release of Neurotransmitters

Sympathetic Nervous System Origin Transmitters Receptors Sympathomimetic drugs Sympathetic Antagonists

Noradrenergic Transmission Classification of Adrenoceptors: -adrenoceptors : Subtypes ( 1 & 2 ) α1 causes vasoconstriction , mydriasis α2 inhibit insulin & renin release

-adrenoceptors : Subtypes ( 1 , 2 & 3 ) β1 increases all cardiac properties ,renin & insulin release & lipolysis β2 vasodilation, relax all non vascular smooth muscles, increase liver & muscle glycogenolysis β3inhibit production of leptin

Classification of Adrenoceptor Agonists A: Catecholamines: epinephrine, norepinephrine, isoproterenol & dopamine.

b) inactivation by COMT MAO enzymes in liver & gut wall. inactivate within other tissues as in liver & gut wall. c) Short duration of action. d) Poor penetration into the C.N.S.

Classification of Adrenoceptor Agonists B: Non Catecholamines: Lacking hydroxyl group. Long half-life. Given orally. . Phenylephrine, ephedrine, amphetamine. Penetrate better to C.N.S.

Classification According to Mechanism of Action 1- Direct-acting Agonists: e.g.: Epinephrine, norepinephrine, isoproterenol, phenylephrine. 2- Indirect-acting Agonists: Taken up into the presynaptic neuron & cause the release of norepinephrine e.g. amphetamine

3- Mixed-acting Agonists: E.g.: Ephedrine

Pharmacological Actions of Sympathomimetic Drugs 1- CVS: 1 (Heart): Positive inotropic &chronotropic &C.O. Increase oxygen demands on the myocardium.

2 : Vasodilation of sketal muscles blood vessels. α1- V.C. of blood vessels in the skin & mucous membranes leading to  in mean blood pressure.

2- Eye: 1 :  mydriasis. In open-angle glucoma decrease production of aqueous humor by vasoconstriction of the ciliary body blood vessels. .

3- Respiratory Tract: 4- GIT: 2 : potent bronchodilator 1: causes vasoconstriction of blood vessels of the upper respiratory tract mucosa  decongestion. 4- GIT: Relaxation of GIT S.M through 2 & 2–

6- Metabolic: 5- Exocrine Glands: Regulate secretion of amylase & water from salivary gland,  sweat production 6- Metabolic: 1) β2 : Hyperglycemia

 Release of glucagon Lipolysis - 2) 2: Decrease insulin release - 3) β3Inhibit the production of leptin by adipose tissue

7- Uterine Smooth Muscle: β2: Delay premature labour through relaxing uterine smooth muscles

8- Genitourinary system α1 :stimulate smooth muscle proliferation in various tissues. E.g.: prostate. β1: stimulate renin secretion α2 : inhibit renin secretion

9- SK.M.: β2 Improve rate & force of contraction used by sport-men to improve performance

10- C.N.S.: Indirect catecholamines have a marked stimulant effect .

Specific Sympathomimetic Drugs Direct Acting: 1- Epinephrine: prototype Stimulates both 1&2 & 1&2 receptors.

Pharmacokinetics - Rapid onset. - Short duration of action. - Given: I.V, S.C, endotracheal tube, inhalation, topically on eye. - Excreted in urine.

Clinical uses 1- Bronchospasm. 2- Anaphylactic shock. 3- Acute asthma (S.C. ). 4- Glaucoma. 2% Topically to reduce I.O.P. in open-angle glaucoma.

5- Cardiac arrest. 6- In anaesthesia with local anaesthetic: a) Increase the duration of L.A. ( by V.C. at the site of injection ). b) Decrease the dose of L.A. c) Decrease the side effects of L.A. d) Control blood oozing of capillary blood ( Local haemostatic effect by V.C. ).

Adverse Effects: 1- C.N.S.: Anxiety, fear, tension, headache, tremor. 2- Hemorrhage: Cerebral hemorrhage as a result of  B.P. 3- Cardiac arrhythmias. 4- Hyperglycemia

2- Norepinephrine: - Acts on all types of adrenergic receptors but mainly on α drenoceptors. - Increase peripheral resistance & both systolic & diastolic B.P. - Reflex bradycardia .

Clinical Uses: I.V.I to treat shock

3- Isoproterenol ( Isoprenaline): Stimulates both 1 & 2. 1-Used in atrioventricular block or cardiac arrest. 2- Acute attack of asthma

Adverse Effects: As epinephrine.

4- Dopamine: Activates α &β adrenoceptors. D1 & D2 dopaminergic receptors vasodilation

Theraplutic Uses: Adverse Effects: 1- Shock (I.V.I.) increase B.P & improves blood flow to viscera. 2- Acute heart failure Adverse Effects: Hypertension, arrhythmias, angina.

Uses: Acute heart failure Adverse Effects: 5- Dobutamine: Selective 1–receptor agonist . Uses: Acute heart failure Adverse Effects:

6- Phenylephrine: - Acts primarily on  mainly 1 receptors. - V.C.   both systolic & diastolic B.P. - Reflex bradycardia .

Topically as nasal decongestant ( produce prolonged vasoconstriction ). Adverse Effects: Hypertensive headache, cardiac irregularities.

7- Clonidine: Is an 2 agonist, used in essential hypertension to lower BP ( action on CNS ). Used to minimize the symptoms of withdrawal from opiates or benzodiazepines .

8- Metaproterenol: - Is not a catecholamines. - Not metabolized by COMT. - Given: orally or by inhalation. - Acts on β1 &β2 mainly on 2–receptors. - Used to treat asthma & bronchospasm.

9- Terbutaline: - Short acting 2 agonist. - By inhalation to treat acute asthma. - Produces less cardiac stimulation.

Indirect-Acting Adrenergic Agonists 1- Amphetamine: - Acts on  &  receptors. - Marked central stimulatory action . a) Attention-deficit hyperactivity disorder of children. b) Narcolepsy(alerting effect &improved attention). c) Appetite control (suppressing effect) as in obesity d) Contraindicated in pregnancy Adverse effects : C.N.S. , Addiction.

2- Methamphetamine: 3- Tyramine: Has a higher CNS effect used as anorexigenic. 3- Tyramine: Found in fermented food as cheese. With MAOI  serious vasopressor Effects causing increasing in B.P.

Mixed-Acting Adrenergic Agonists 1- Ephedrine: ( a plant alkaloid ) Indirect & direct acting on  &  receptors. - Similar to epinephrine but less potent. - Not a catecholamine drug. Long duration. C.N.S. stimulant better than epinephrine.

- Absorbed well orally. - Used as prophylactic in chronic asthma.

- Enhances skeletal muscle contractility & improves motor function in myasthenia gravis. - Mild stimulation to CNS  alertness,  fatigue, insomnia. - Improves athletic performance. - Nasal decongestant.  BP.

Ephedrine (cont.) Is useful in the treatment of stress incontinence. Pseudoephedrine(stereoisomer of ephedrine) used orally for the relief of nasal congestion. Less potent than ephedrine in producing tachycardia, hypertension, C.N.S. stimulation. Used in the treatment of stress incontinence.

Classification of -receptor Antagonists * non-selective e.g. phenoxybenzamine & phentolamine. * 1-selective antagonists e.g. prazosin/ terazosin, doxazosin. * 2-selective antagonists e.g. yohimbine, idazoxan.

Non-Selective - Adrenoceptor Antagonists Phenoxybenzamine: Blocks both 1 and 2 irreversibly . Blocks the action of histamine ,Ach & 5HT. Long-acting (24hrs).

Phentolamine: Produces a competitive blocking of 1 & 2 receptors.-short acting (few hrs). Both drugs cause: 1) Postural hypotension. 2) Reflex tachycardia.

- Increase in C.O. & H.R. ( reflex response to the fall in B.P, mediated through - adrenoceptors, also due to block 2 in heart ).

N.B.: The block of 2–adrenoceptors increase in noradrenaline release which make the drug unsuccessful in maintaining lowered blood pressure.

Therapeutic Uses: 1- Pheochromocytoma. 2- Raynaud,s disease.

Adverse Effects: - Phenoxybenzamine causes postural hypotension, nasal stuffiness, nausea, vomiting, impotence, tachycardia. - Phentolamine: As phenoxybenzamine but more to induce cardiac arrhythmias and anginal pain. Both are contra-indicated in patients with decreased coronary perfusion.

Selective 1- Antagonists Prazosin (short half-life) ,doxazocin& terazocin (long half life )allowing once- daily dosing. 1–antagonists cause vasodilatation & fall in arterial pressure, but less tachycardia than with non- selective  blockers.

Selective 1- Antagonists 2- relaxation of the smooth muscles of the bladder neck & prostate capsule, which may be useful in patients with urinary retention due to prostate hypertrophy. E.g. tamsulosin

Selective 2- Antagonists Yohimbine is a natural alkaloid. Idazoxan is a synthetic drug. Inhibit insulin secretion, used in the treatment of diabetes . in the treatment of peripheral vascular diseases.

Adverse Effects of 1 &α2 Blockers: Dizziness, lack of energy, nasal congestion, headache, drowsiness, postural hypotension. Impotence or sexual dysfunction .

- Adrenoceptors Antagonists Drugs Classification: a) Non selective: e.g. propranolol, carvedilol, labetalol, sotalol, timolol. b) Selective(1): Atenolol, bisoprolol, esmolol, metoprolol

Pharmacokinetis of –blockers: a) Absorption: Most of them are well absorbed orally.

c) Distribution : They are rapidly distributed, propranolol cross readily BBB. Most of them have half-life from 3-10hrs except esmolol (10min.)

Most of them metabolized in liver & excreted in urine.

Pharmacodynimcs of –Adrenoceptors Antagonists : * Blocking the β-receptors. Local anaesthetics Partial agonist action

Pharmacological Actions: CVS: Negative inotropic & chronotropic effects.  BP . * Respiratory tract: Blockade of 2  bronchoconstriction.

* Eye: Reduce intraocular pressure (In open-angle glaucoma) due to  aqueous humor production from the ciliary epithelium e.g. timolol.

Metabolic & endocrine effects: - Inhibit lipolysis , glycogenolysis & decrease glucagon secretion. Increased Na+ retention.

* Effects not related to beta blockade: - Partial -agonist activity. - Local anaesthetic action ( blockade on sodium channels).

Clinical Uses of –receptor Blocking Drugs: 1) Hypertension: Labetalol a competitive , antagonsits is effective in hypertension. -blockers are less effective in blacks & the elderly.

2) Ischemic heart disease: - Reduce the frequency of anginal episodes. - Improve exercise tolerance. - Decrease cardiac work & oxygen demand. - Reduce heart rate.

3) Cardiac arrhythmias: In supraventricular & ventricular arrhythmias. Sotalol has potassium channel blockade in addition to its –blockade

4) Other cardiovascular disorders: - Chronic heart failure with metoprolol, & carvedilol ( myocardial remodeling &  risk of sudden death).

5) Glaucoma:  I.O.P. Through  the production of aqueous humor by the cliliary body, which is activated by cAMP. Timolol & related -antagonists are suitable for local use in the eye because they lack local anaesthetic properties.

Systemic timolol may be absorbed from the eye to cause serious adverse effects on the heart & airways. Topical timolol may interact with orally administered verapamil & increase the risk of heart block.

6) Hyperthyroidism: To diminish catecholamine action which play an important part of the patho- physiology of the disease.

7) Neurologic disease: - Chronic migraine :blockade of catecholamine-induced vasodilation -

Adverse Effects & Toxicity of - Adrenoceptors Antagonists Bronchoconstriction -Arrhythmias -Sexual impairment -Hypoglycemia

Choice of –adrenoceptor antagonists: - (Cardioselective β blockers are preferred in insulin –dependent asthmatics.). Choice of –adrenoceptor antagonists: 1- Pindolol & acebutolol. with partial agonist activity. [ Intrinsic sympathominetic activity ISA ].

- They have the ability to stimulate 1 & 2 receptors.

- They are effective in hypertensive patients with moderate bradycardia. - Carbohydrate metabolism is less affected , making them valuable in treatment of diabetics.

2- Labetalol & carvedilol. Antagonists of both  &  adrenoceptor blockers. Are reversible -blockers with concurrent 1-blockers that cause peripheral vasodilatation  B.P effective for treatment of hypertension in patients with increased peripheral vascular resistance.

They do not alter serum lipid or blood glucose levels. Used in the treatment of heart failure

Adverse Effect: Labetalol may by used as an alternative to hydralazine in the treatment of pregnancy-induced hypertension. Treatment of hypertensive emergencies as it is rapidly lowering B.P. Adverse Effect: Orthostatic hypotension & dizziness are associated with 1-blockade.

Nonselective β Antagonists Timolol ,Propranolol, nadolol Blocks both β1 & β2 receptors. Timolol & Pindolol are more potent than propranolol. Nadolol has a very long duration of action.

Selective β1 Antagonists Acebutolol, Atenolol, Metoprolol, Esmolol They have little effect on pulmonary function ,peripheral resistance ,& carbohydrate metabolism. Esmolol has a very short duration of action and given only I.V.

Also, are effective in diabetic hypertensive patients . Therapeutic uses They are useful in hypertensive patients with impaired pulmonary function. Also, are effective in diabetic hypertensive patients .

Drugs Affecting Neurotransmitter Release or Uptake 1- Reserpine: Depletion of norepinephrine levels in the adrenergic neurons.

Hypertensive patients show a gradual decline in B.P & H-R. Reserpine has a slow onset & long duration of action.

2- Guanethidine: Blocks the release of stored norepinephrine. This lead to gradual Drop in B.P & H-R. Used in the treatment of hypertension.

Guanethidine causes orthostatic hypotension & male sexual dysfunction.

3- Cocaine: Has a local anaesthetic action by blocking sodium channels across the cell membrane of the adrenergic neuron.

Norepinephrine accumulates in the synaptic space resulting in the potentiation of the actions of Sympathomimetics. Cocaine is a C.N.S stimulant drug.